Lysosomal system and neurotrophic support defects In Alzheimer's disease (AD), and Down's syndrome (DS) are accompanied by altered expression of endocytosis-related genes. Triplication of App in DS cells causes similar endocytic pathway dysfunction mediated by the B C-terminal APP fragment (liCTF), independent of A&. This endosomal phenotype is associated with retrograde neurotrophic support failure and degeneration of basal forebrain cholinergic neurons (BFCNs). We propose to identify specific genes and their proteins In an interrelated pathway that consists of APP/APP metabolites and endosomal signaling effectors that impinge upon AD pathology-related processes including endosomal-lysosomal trafficking, autophagy, neurotrophic signaling, and cell cycle reentry defects in vulnerable septohippocampal neurons. We will target genes and proteins that link the abnormal endosomal phenotype to neurodegeneration In vulnerable BFCNs and CAI neurons in relevant animal models and human brains, including both App-dependent and App-independent pathways. In Aim 1 we will identify discrete expression changes related to APP/BCTF and neurotrophin signaling pathways in BFCNs In trisomic mice and following fimbria-fornix (FF) transections in wild type mice before and after exogenous NGF rescue. In Aim 2 we will define key players in an aberrant signaling pathway leading from abnormal endosomal phenotype to neurodegeneration in vulnerable versus less vulnerable neurons within the septohippocampal circuit. In Aim 3, we hypothesize that APP overexpression in FAD and DS is mediated through BCTF and involves a rab5-driven pathway to neurodegeneration. Using a novel rab5 mouse model, we will determine whether rab5 up regulation is necessary and sufficient to cause endosomal dysfunction and neurodegeneration, or whether APP/ISCTF signaling is also required. Genetic manipulations of APP, BCTF, and rab5 levels In mice, coupled with qPCR in vulnerable cells acquired by LCM and immunocytochemistry for cell death markers are predicted to identify gene changes associated with interrelated APP/BCTF- and rab5-inifiated signaling cascades, thus identifying new potential therapeutic targets within these key pathways that initiate neurodegeneration.